Nerve growth factor (NGF) is a neurotrophic factor in mammals whose induction is triggered by various physiological perturbations to the nervous system, including nerve lesions and excitotoxic destruction. As a result of such perturbations, nearby glial and fibroblast cells may increase production of NGF. In turn, NGF promotes neuronal survival by initiating a signal transduction cascade, which begins with the binding of NGF to specific receptors on the surface of neuronal cells.
Therapy employing NGF has been suggested as a method of preventing or reducing the atrophy and loss of neuronal cells that may occur during a stroke or in neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Huntington's disease. However, since NGF itself cannot cross the blood-brain barrier, exogenous NGF would have to be administered directly into the brain. Obviously, the need for such a process severely limits the therapeutic potential of exogenous NOF treatment. However, a promising alternative is endogenous NGF treatment; this alternative depends on the possibility of inducing—i.e., stimulating—the production of NGF within the brain. The development of small-molecule inducers of endogenous NGF would allow the full potential of NGF therapy to be exploited. In experiments with astrocytoma cells, cyathin A3 and the structurally similar products erinacine C and scabronine A have demonstrated significant NGF-inducing activity. Elucidating the mechanism by which these compounds induce NGF is expected to aid significantly in the future development endogenous NGF therapy.
In the 1970s, H. J. Brodie and coworkers reported production of cyathin A3 by Cyathus helenae strain 1500. In Brodie's most preferred method, yields of approximately 130 μg/mL cyathin A3 were reported as resulting from the use of static liquid cultures with 30 mL media (30 g/L glucose, 1.5 g/L asparagine, 1 g/L KH2PO4, 0.5 g/L Ca(NO3)2.4H2O, 0.5 g/L MgSO4.7H2O, 0.25 mg/L ZnSO4.2H2O, and 0.15 mg/L thiamine) in a 125 mL flask, inoculated with a 8 mm diameter agar plug of fungal mycelium (obtained from the edges of a 5 day old culture), and incubated at room temperature for 30 days. However, this method has been plagued by low yields and poor reproducibility.